Researchers have successfully isolated 18 bacterial strains from the stool of healthy individuals, showing promise as a potentially more effective treatment for gut infections that are resistant to antibiotics. The research team discovered that these strains can inhibit the growth of Enterobacteriaceae bacteria and reduce inflammation in mice’s intestines by competing with harmful bacteria for carbohydrates, thus preventing their colonization. These results may pave the way for creating a targeted microbial transplant for patients, offering a safer alternative to existing treatments that combat antibiotic-resistant bacteria.
Patients with chronic inflammatory bowel conditions, like inflammatory bowel disease, or those who have undergone long-term antibiotic treatments often face antibiotic-resistant bacterial infections. A prevalent cause of these infections is Gram-negative bacteria, such as Enterobacteriaceae, for which treatment options are limited. While fecal microbiota transplants have shown potential in addressing some of these infections, their effectiveness can vary considerably due to differences in composition.
Scientists from Keio University School of Medicine in Tokyo and the Broad Institute of MIT and Harvard have discovered 18 bacterial strains from healthy individuals that could serve as a more effective therapy. The research indicated that these strains hinder the growth of Enterobacteriaceae and reduce inflammation in mice guts by competing with harmful bacteria for carbohydrates and blocking them from establishing themselves in the intestines.
The results, published in Nature, suggest the potential for developing a microbial transplant that manages antibiotic-resistant bacteria in a more mannered fashion, inducing fewer side effects compared to existing treatments.
“After two decades of exploring the microbiome, we are just starting to grasp the health-enhancing aspects of gut microbes,” stated Marie-Madlen Pust, a computational postdoctoral researcher at Broad and co-lead author of the study.
“Each individual’s microbiome is unique, which complicates our understanding. This collaborative research enabled us to functionally analyze the varying mechanisms these bacteria utilize to minimize pathogen load and gut inflammation,” she added.
Ramnik Xavier, co-senior author of the study and a key member of the Broad Institute, pointed out, “Microbiome studies often involve analyzing genetic sequences without a clear understanding of the functions of each gene or what makes certain microbes beneficial. Discovering that function is the next challenge, and this research takes an important step towards understanding how microbial metabolites impact health and inflammation.”
Pust is part of Xavier’s lab, who co-directs its Infectious Disease and Microbiome Program. Xavier holds the Kurt J. Isselbacher Professorship of Medicine at Harvard Medical School, serves as director of the Center for Computational and Integrative Biology at Massachusetts General Hospital (MGH), and co-directs the Center for Microbiome Informatics and Therapeutics at MIT.
Kenya Honda from the Keio University School of Medicine serves as the study’s co-senior author. Co-first authors include Munehiro Furuichi, Takaaki Kawaguchi, and Keiko Yasuma-Mitobe, all of whom are researchers at Keio University. This study utilized specialized culture techniques and animal models by Honda’s lab to investigate bacterial infections, while the Xavier lab focused on developing software to analyze unknown microbial metabolites.
Bacterial balances
Antibiotic-resistant Enterobacteriaceae like E. coli and Klebsiella are frequently found in hospitals. They can thrive in patients’ intestines and lead to severe systemic infections that are challenging to treat. Some studies indicate that Enterobacteriaceae may also contribute to intestinal inflammation and enable infections from other microbes. Honda, Xavier, and their teams aimed to identify specific bacteria from fecal microbiota transplants that could shield the intestinal microbiome from Enterobacteriaceae. Honda’s team isolated around 40 different bacterial strains from stool samples from five healthy individuals and employed them to treat mice infected with either E. coli or Klebsiella. They tested various strain combinations and pinpointed 18 strains that most effectively suppressed Enterobacteriaceae.
The researchers observed that in Klebsiella-infected mice treated with these 18 beneficial strains, Klebsiella altered gene expressions related to carbohydrate uptake and metabolism, including a reduction in gluconate kinase and transporter genes—indicating increased competition among gut microbes for nutrients.
Xavier’s team sought to analyze samples from patients with and without gut inflammation. Collaborating with the Broad’s Metabolomics Platform, directed by senior author Clary Clish, they examined samples from pediatric patients with ulcerative colitis to detect alternate gluconate pathway genes in gut microbes and levels of fecal gluconate. Results showed elevated gluconate levels associated with higher gluconate-consuming Enterobacteriaceae in samples from pediatric patients experiencing ongoing inflammation, indicated by elevated calprotectin protein levels.
The collective findings suggest that Enterobacteriaceae uses gluconate as a crucial nutrient, exacerbating inflammation in patients. However, with the addition of the 18 helpful strains in the gut microbiome, they likely compete against Enterobacteriaceae for gluconate and other nutrients, curtailing the growth of the harmful bacteria.
Additionally, these 18 strains did not interfere with the growth of other beneficial bacteria in mice carrying gut microbes from patients with Crohn’s disease and ulcerative colitis, further supporting their potential as a therapy.
While further research is necessary to fully understand the mechanisms that allow different bacteria to compete, these findings indicate that microbial treatments could adjust the gut’s ecosystem and combat harmful bacterial infections with fewer adverse effects compared to conventional antibiotic treatments.
The research team is also focused on identifying and understanding the roles of unknown metabolites that play a part in promoting gut health and managing inflammation.
